With the use of multi-drug regimens including protease inhibitors, the prognosis for HIV infection has greatly improved. However, a high proportion of patients develop metabolic complications including insulin resistance, hyperlipidemia, and body fat redistribution (HIV-LD). Although these metabolic abnormalities undoubtedly arise from multiple factors, the hypothesis of this proposal is that loss of peripheral adipose tissue, diminished insulin sensitivity, and hypertriglyceridemia are the result of a reduction in the native ligands for the peroxisome proliferator-activated receptor (PPAR) system in adipose tissue, skeletal muscle, and liver. Patients with HIV-LD have decreased expression of both PPAR gamma and PPAR alpha -regulated genes. Specific Aim 1 will document alterations to the expression of genes regulated by the SREBPs and PPARs in both adipose and muscle tissue and document serum profiles and levels of apolipoproteins that PPAR alpha in liver. Gene expression, determined with real time- PCR, will be related to insulin sensitivity from a hyperinsulinemic, euglycemic clamp, and loss of peripheral fat documented with CT and DEXA. We have shown that treatment with rosiglitazone, a ligand for PPAR gamma, partially restored both insulin sensitivity and peripheral adipose tissue, suggesting a decline in the native PPAR ligand in HIV-LD. We hypothesize that reduced PPARalpha activity in the liver contributes to the hypertriglyceridemia in HIV-LD. Specific Aim 2 will determine the enhanced expression of genes involved in adipocyte, liver, and skeletal muscle fat metabolism associated with agonists of PPAR gamma (rosiglitazone) and PPAR alpha (fenofibrate). Improved adipose differentiation will be related to improved insulin sensitivity and to an improvement in serum lipids and ApoCIII levels, a measure of enhanced activity of PPAR alpha. The ability of agonists of PPAR alpha and gamma, to improve gene expression for adipocyte differentiation, to improve metabolism of triglycerides, and to improve insulin sensitivity will support the hypothesis that a reduction in PPAR ligand is responsible for these metabolic abnormalities. Understanding the abnormalities in gene expression responsible for the alterations in metabolism associated with antiretroviral therapy may lead to the development of more specifically targeted drugs to repair these metabolic defects and to reduce the risk of cardiovascular disease.